Estrogens, including diethylstilbestrol (DES), were used as the primary medical treatment for metastatic prostate cancer for many years but have been superceded in the past two decades by luteinizing hormone-releasing hormone (LHRH) agonists, primarily because of the cardiovascular toxicity associated with oral estrogen therapy. Recently, a renewed interest in estrogen therapy for prostate cancer in the United States has developed as a result of 3 major issues. First, when measured by declines in prostate-specific antigen of > or = 50%, clinical trials have demonstrated activity of DES, DES-diphosphate, and the estrogenic herbal therapy PC-SPES in 21%-86% of patients treated in phase II trials of androgen-independent prostate cancer patients. Second, the recent description of estrogen receptor (ER)-b has led to a reevaluation of the role of estrogens in normal prostate development and cancer pathogenesis. In contrast to ER-a, ER-b is strongly expressed in normal prostate epithelium. Furthermore, loss of ER-b expression has been demonstrated in prostate cancers, suggesting a possible role for this pathway in the development of cancer. Finally, the issues of cost and safety of estrogens are being reassessed in the current environment of rising health care costs and improved cardiovascular care. In Europe, estrogen therapy is more accepted as a low-cost and effective alternative to LHRH agonists and antiandrogens. Toxicity of DES and other estrogens has also been attenuated by strategies that use lower doses and parenteral routes of administration, thereby avoiding hepatic first-pass metabolism and decreasing the risk of thromboembolism. Nonetheless, there remain many unanswered questions about the role of estrogen therapy in prostate cancer, including differences between specific drugs, optimal dose, timing, and patient selection. Further research is needed.